title: A novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered Tau function.
abstract: Over two dozen mutations in the gene encoding the microtubule associated protein tau cause a variety of neurodegenerative dementias known as tauopathies, including frontotemporal dementia (FTD), PSP, CBD and Pick's disease. The vast majority of these mutations map to the C-terminal region of tau possessing microtubule assembly and microtubule dynamics regulatory activities as well as the ability to promote pathological tau aggregation. Here, we describe a novel and non-conservative tau mutation (G55R) mapping to an alternatively spliced exon encoding part of the N-terminal region of the protein in a patient with the behavioral variant of FTD. Although less well understood than the C-terminal region of tau, the N-terminal region can influence both MT mediated effects as well as tau aggregation. The mutation changes an uncharged glycine to a basic arginine in the midst of a highly conserved and very acidic region. In vitro, 4-repeat G55R tau nucleates microtubule assembly more effectively than wild-type 4-repeat tau; surprisingly, this effect is tau isoform specific and is not observed in a 3-repeat G55R tau versus 3-repeat wild-type tau comparison. In contrast, the G55R mutation has no effect upon the abilities of tau to regulate MT growing and shortening dynamics or to aggregate. Additionally, the mutation has no effect upon kinesin translocation in a microtubule gliding assay. Together, (i) we have identified a novel tau mutation mapping to a mutation deficient region of the protein in a bvFTD patient, and (ii) the G55R mutation affects the ability of tau to nucleate microtubule assembly in vitro in a 4-repeat tau isoform specific manner. This altered capability could markedly affect in vivo microtubule function and neuronal cell biology. We consider G55R to be a candidate mutation for bvFTD since additional criteria required to establish causality are not yet available for assessment.
authors.affiliation: Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, United States of America.
authors.forename: Abhinaya
authors.initials: A
authors.lastname: Iyer
authors.forename: Nichole E
authors.initials: NE
authors.lastname: Lapointe
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Zielke
authors.forename: Mariusz
authors.initials: M
authors.lastname: Berdynski
authors.forename: Elmer
authors.initials: E
authors.lastname: Guzman
authors.forename: Anna
authors.initials: A
authors.lastname: Barczak
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Chodakowska-Żebrowska
authors.forename: Maria
authors.initials: M
authors.lastname: Barcikowska
authors.forename: Stuart
authors.initials: S
authors.lastname: Feinstein
authors.forename: Cezary
authors.initials: C
authors.lastname: Zekanowski
mesh_terms: D000595:Amino Acid Sequence; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D011044:Poland; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins